Separation process

ABSTRACT

A process is described for separating a desired substance from an aggregate mixture in which process a three-phase dispersion is formed, the first phase comprising droplets phase comprising a liquid transport phase, and the third phase comprising a surface upon which the desired substance can crystallize, whereby a chemical potential exists for crystal growth of the desired substance in the third phase thereby creating a flow of the desired substance from the first phase through the second phase to the third phase where the desired substance crystallizes, characterized in that the Gibb&#39;s free enthalpy of formation (ΔG) of the droplets is &lt;0.

The invention described herein is in the field of separation processesand relates particularly to a crystallisation process for separating adesired substance from an aggregate mixture of substances.

BACKGROUND OF THE INVENTION

Conventional crystallisation involves the saturation of a solvent with asolid material, followed by the induction of supersaturation by loweringthe temperature or by evaporation of solvent. The crystallisationvelocity can be influenced by the rate of cooling or evaporation, i. e.by the degree of distortion of the thermodynamic equilibrium.

The crystallisation rate—or in equilibrium stage the rate of exchange ofmolecules at the crystal surface—is very high in a conventionalcrystallisation process and the probability that a “wrong” molecule getstrapped by other molecules is considerable. Therefore, the conventionalcrystallisation process reflects only to a very limited extent themaximum possible differences in adsorption energies of differentmolecules on a certain crystal surface, as is sometimes the case withoptimised chromatographic processes, and to a certain extent a highlydynamic situation of “trapping molecules” by the layers of the crystalthat successively form.

The purification of mixtures of compounds by emulsion crystallisation isknown. In emulsion crystallisation processes, mixtures are purified byforming emulsified droplets of the mixtures and then adding seedcrystals of one component of the mixture to thereby selectivelycrystallise that component, or by cooling the emulsion to inducecrystallisation (c.f. EP 0 548 028 Al; Davey et al., Nature, Vol. 375,pp. 664-666 (Jun. 22, 1995); I. Holéci, Chemicky prûmysi 14/39, pp.638-641 (1964)).

Though these emulsion crystallisation processes are effective, theypossess certain disadvantages. First, the formation of the emulsionsrequires high-shear equipment, which can be undesirable from aprocessing standpoint. Second, as the emulsions tend to bethermodynamically unstable, the emulsion droplets tend to coalesce or“oil out”. In addition, the droplet size contemplated (typically 0.5-50μm) is large enough to allow undesirable spontaneous crystallizationwithin the droplet with certain types of mixtures.

DETAILED DESCRIPTION OF THE INVENTION

The crystallisation process described herein is directed to a processfor separating a desired substance from an aggregate mixture in whichprocess a three phase dispersion is formed, the first phase comprisingdroplets containing the aggregate mixture, the second phase comprising aliquid transport phase, and the third phase comprising a surface uponwhich the desired substance can crystallise, whereby a chemicalpotential exists for crystal growth of the desired substance in thethird phase thereby creating a flow of the desired substance from thefirst phase through the second phase to the third phase where thedesired substance crystallises, characterised in that the Gibb's freeenthalpy of formation (ΔG) of the droplets is <0. Such droplets formspontaneously, are thermodynamically stable and are small enough toprevent spontaneous crystallisation within them.

The first and second phases of the process according to the presentinvention together form what is known in the art as a microemulsion.Microemulsions provide the significant advantage that their droplets aretypically transparent which facilitates observing and monitoring eachspecific crystallization process.

In addition, the droplets of a microemulsion provide an interfacebetween the first and second phases having a significantly increasedsurface in comparison to macroemulsions. Larger surface areas enablehigher flow rates of substance from the first to the second phase, andthereby, higher rates of crystallization. Higher crystallization ratesare advantageous from the standpoint of the scale-up andcommercialization of a process.

The process according to the present invention may be carried out inbatch or continuous operation.

“Desired substance” as used herein, refers to inorganic and organicsubstances having a melting point above −130° C., preferably above −78°C., more preferably above −20° C. The process of this invention isespecially indicated for those substances that have been traditionallydifficult to purify, e.g. constitution isomers, stereo isomers i.e.cis/trans isomers, diastereomers, enantiomers etc. and homologues. Thedesired substance can be a pharmaceutical, an agrochemical, a fragrance,a food additive, a chemical intermediate or the like.

“Aggregate mixture” as used herein refers to a mixture containing thedesired substance and one or more impurities. The aggregate mixture maybe a liquid or a solid, or a liquid and a solid. The aggregate mixturemay be optionally dissolved or dispersed in one or more solvents.Droplets of the aggregate mixture are typically formed with the aid ofone or more alcohols, whereby the alcohol may be added externally to thedispersion, or may be contributed by the aggregate mixture itself.

In addition, formation of droplets may also be aided by one or moresurface active agents, hereinafter described. The surface active agentsmay be added externally to the dispersion, or may be contributed by theaggregate mixture itself.

The droplets will have a diameter of less than 500 nm, and preferablyless than 200 nm, e.g. 5-200 nm. Droplets of this dimension create in adispersion what is commonly referred to in the art as a microemulsion.

Due to the Gibb's free enthalpy of formation (ΔG) being <0, the dropletswill form spontaneously in the second phase, hereinafter described.Formation of these droplets may, however, be accelerated through the useof agitation, e.g. gentle stirring, shaking, pumping or ultrasound.

It is to be understood that the aggregate mixture nay contain one ormore desired substances. The desired substances may, according tochoice, be separated from the aggregate mixture either individually orsimultaneously.

The second phase of the system, which functions as a transport phasethrough which the desired substance flows before crystallising onto thethird phase, is liquid and will be selected based upon the solubilitycharacteristics, nucleation characteristics and the selectivity of thecrystallisation process for the desired substance. Preferably thedesired substance will be less soluble in the second phase than in thefirst phase.

In such cases where the desired substance is water insoluble orsubstantially water insoluble, the second phase is conveniently polarand hydrophilic.

The second phase may further contain an-agent for adjusting thesolubility of the desired substance in the second phase and/or thefreezing point of the second phase. In such cases where the second phaseis water, such agent is conveniently a water soluble inorganic salt suchas CaCl₂, NaCl, KCl, MgCl₂ AlCl₃, or a water-miscible organic liquidsuch as an alcohol, ether, ketone, ester, lactone, dimethylsulfoxide(DMSO) and acetonitrile. Water-miscible organic liquids are preferred.

Below is set forth a list of suitable solvents and solvent additives tobe used in the first phase or the second phase.

I. Non-polar, lipophilic solvents and additives having a watersolubility of ≦5% v/v at room temperature (hereinafter “r.t.”) include:

1. Alkanes such as n-, i- or branched of the general formula—(C_(n)H_(2n+2))— including polyethylenes, polypropylenes, cycloalkanes(e.g. cyclopentane, cyclohexane);

2. Alkenes such as n-, i- or branched of the general formula—(C₂H_(2n))— including cycloalkenes (cyclohexene, terpene), di- orpolyalkenes;

3. Alkines such as n-, i- or branched of the general formula—(C_(n)H_(2n−2))—, cycloalkines, di- or polyalkines;

4. Aromatics such as unsubstituted aromatics (e.g. benzene,naphthalene), substituted aromatics such as alkylated aromatics (e.g.toluene, xylene, higher alkylated benzenes, alkylated naphthalenes),heterosubstituted aromatics such as halogenated (e.g. chlorobenzene,hexafluorobenzene) and/or nitrated (e.g. nitrobenzene), heteroaromaticssuch as pyridine, furane, thiophene, and polymers such as polystyrene;

5. Mineral-, synthetic-, crop- and/or silicone oils (e.g. Castor oil,methyloleate, polysiloxane);

6. Halogenated hydrocarbons such as CH₂Cl₂, CHCl₃, CCl₄,trichloroethane, trichloroethene, polyvinylchloride;

7. CS₂, CO₂;

8. Ethers such as n-, i- or branched of the general formula(C_(n)H_(m))O(C_(x)H_(y)) with total C≧4 (e.g. diethylether, tert-butylmethylether (TBME);

9. Aldehydes such as n-, i- or branched of the general formulaC_(n)H_(m)CHO with total C≧4.

10. Ketones such as (C_(n)H_(m))CO(C_(x)H_(y)) with total C≧6 (e.g.2-hexanone, methyl-t-butylketone) or cycloketones with approx. C≧6;

11. Esters such as n-, i- or branched of the general formula(C_(n)H_(m))COO(C_(x)H_(y)) with total C≧5, diesters such as di(-methyl-isodecyl-, -isodecyl-, -isotridecyl-) phthalate, diesters of carbonicacid, triesters such as oils and fats, and polyesters;

12. Amides such as N-,N-dimethyl laurylamide, and polyamides;

13. Lactames such as (N-octyl-, N-dodecyl-)pyrrolidone;

14. Alkanoles, alkenoles, alkinoles, aromatic and cyclic alcohols suchas n-, i-, branched or cyclic of the general formula (1,2, . . . )(C_(n)H_(m))OH with total C≧5 (e.g. 2-hexanol, cyclohexanol,benzylalcohol and terpinol);

15. Primary, secondary and tertiary amines e.g. n-, i- or branched ofthe general formula (1,2, . . . ) (C_(n)H_(m))NH₂ with total C≧6 (e.g.dodecylamine);

II. Amphiphilic solvents, soluble in both non-polar, lipophilic andpolar, hydrophilic phases with a water solubility of >5% v/v at r.t. anda solubility of >5% v/v at r.t. in methyloleate include:

1. Ethers such as tetrahydrofurane (THF), polyethers such as(dimethoxyethane (DME), dioxane, trioxane, polyethylene glycol (PEG),polypropylene glycol (PPG);

2. Alcohols such as n-,i-, cyclo- or branched of the general formula(1,2, . . . ) (C_(n)H_(m)) OH with total C≦5 (e.g. isopropanol,isobutanol, cyclobutanol, cyclopentanol), aromatic alcohols such asphenol, furfurylalcohol, diols such as propyleneglycol, butanediol,hydrochinone or polyols;

3. Aminoalcohols such as ethanolamine, diethanolamine, triethanolamine;

4. Primary, secondary and tertiary amines such as n-, i- or branched ofthe general formula (1,2, . . . )(C_(n)H_(m)) NH₂ with total C≦7(aniline, cyclohexylamine, pyridine, morpholine), polyamines;

5. Aldehydes with total C≦3 (e.g. formaldehyde, acetaldehyde);

6. Ketones such as n-, i- or branched of the general formula(C_(n)H_(m)) CO (C_(x)H_(y)) or cyclic ketones with total C≦6 (acetone,2-butanone, cyclohexanone);

7. Esters such as n-, i- or branched of the general formula (C_(n)H_(m))COO (C_(x)H_(y)) with total C≦4, di-, triesters ethylenglycoldiacetate,dimethyladipiate, dimethylglutamate, dimethylsuccinate,trimethylphosphate);

8. Lactones such as γ-butyrolactone;

9. Amides such as formamide, dimethyl formamide (DMF), acetamide;

10. Lactames such as (N-methyl-, N-ethyl-, N-isopropyl-, N-hydroxyethyl-) pyrrolidone;

11. Other heterocyclic compounds such as imidazoles, triazoles;

12. Carbon-acids such as n-, i- or branched of the general formulaC_(n)H_(m)COOH with total C≦5.

III Polar, hydrophilic solvents or solvent additives with a solubilityof ≦5% v/v in methyloleate include:

1. Water;

2. DMSO;

3. Di- or polycarbonic acids (e.g. oxalic acid, tartaric acid);

4. selected di- or polyalcohols (e.g. ethanediol, glycerine, PVA);

5. Amino acids;

6. Sugars.

IV. Chiral solvents and additives include: camphene, menthol, fenchone,nicotine, ephedrine, 2-amino-1-butanol, mandelic-acid and esters, lacticacid and esters, camphoric acid and esters, camphene-10-sulfonic acidand esters, Mosher's acid, tartaric acid and esters such as mentyl-,dodecyl-, natural and artificial α-amino acids and derivates, sugars andderivates (e.g. vitamin C).

For embodiments of the present invention-employing an oil-in-water (o/w)dispersion, microemulsion droplets are advantageously formed with theaid of one or more alcohols added to the dispersion. Such alcoholsinclude iso-butanol, 1-butanol, 2-butanol, 2-pentanol, 2-hexanol,2-octanol, cyclopentanol, cyclohexanol, benzylalcohol, terpineol andfurfurylalcohol. These alcohols will be present in the dispersion in anamount ranging from 2-80% by weight, preferably 3-50%, more preferably5-40%,

Formation of the microemulsion droplets in o/w dispersions may also beaided by adding one or more nonionic and/or anionic surfactants to thedispersion. Nonionic surfactants include ethoxylated castor oils, sugaresters, sugar ethers, ethoxylated alkanols, ethoxylated alkylphenols,acetylenic diols (e.g. 2,4,7,9 tetramethyl-5-decyn-4,7-diol). Anionicsurfactants include alkylarenesulfonates e.g. dodecylbenzenesulfonates,sulfosucciantes, e.g. dioctylsulfosuccinates, (ethoxylated)alkylsulfates (e.g. laurylsulfate, laurylethersulfates), [mono- or di-(tristyrylphenyl)]phosphates. The surfactants may be present in thedispersion in an amount ranging from 1-60% by weight, preferably 3-40%,more preferably 5-30%.

Further optional additives to o/w dispersions include toluene, xylene,chlorobenzene, nitrobenzene and aniline, in amounts ranging from 3-40%by weight of the dispersion, preferably 5-20%, together withN-(methyl-,ethyl- or propyl-) pyrrolidone, trimethylphosphate, DMSO, DMFdimethylacetamid and THF in amounts ranging from 5-60% by weight of thedispersion, preferably 10-40%,

The third phase of the system comprises a surface upon which the desiredsubstance can crystallise. Typically this surface will comprise or beformed from crystals of the desired compound, which are convenientlyintroduced into the system by seeding with the desired compound or byspontaneous crystallisation of the desired compound due to the chemicalpotential for such crystallisation.

The three phase system according to the present invention willpreferably contain one or more surface active agents, i.e. solubilizers,surfactants and/or dispersants which assist in forming and stabilizingthe microemulsion droplets of the first phase and the crystals of thethird phase. Such solubilizers, surfactants and/or dispersants will bechosen according to the nature of the dispersion, and can be nonionic,anionic and/or cationic.

Below is set forth a non-exhaustive list of suitable solubilizers,surfactants and dispersants:

I. Non-ionic surfactants including ethoxylated or ethoxylated andpropoxylated [alkylphenols, di- or tristyrylphenols, oils (e.g. castoroils), oleic acids, fatty or synthetic alcohols, fatty or syntheticamines or amides]; ethoxylated or ethoxylated and propoxylated sugaresters (e.g. sorbitan monolaurate, POP-POE glycerol sorbitan fattyesters) of e.g. (ethoxylated) oleic or fatty acids; sucroglycerides;ethoxylated sugar ethers (e.g. alkyl polyglucoside); siliconesurfactants (e.g. silicone glycol copolymers with polyoxyalkylenepolymethylsiloxane units; acetylenic diols (e.g.2,4,7,9-tetramethyl-5-decyn-4,7-diol); polyethylene oxide/polypropyleneoxide copolymers; acrylic polymers; polyvinyl alcohol; modifiedpolyesters.

II. Anionic surfactants including alkylarene sulphonates (eg. dodecylbenzene sulfonates); alkyldiphenyl ether sulfonate salts;sulfosuccinates (eg. dioctyl sulfosuccinates); (ethoxylated) alkylsulfates (e.g. lauryl sulfates, lauryl ether sulphates); (fluorinated)mono-, di- and/or triesters of phosphorous acid and salts thereof (asalcohols may be used e.g. (ethoxylated) alkyl-, di- or tristyrylphenols,alkanols such as C₈-₁₈—OH, 2-ethylhexyl- or lauryl alcohol); ethoxylateddi- or tristyrylphenol sulfates.

III. Cationic surfactants including protonated (ethoxylated) primary,sec., or tert. amines or diamines: (ethoxylated) quarternary ammoniumsalts (e.g. trimethyl oleyl ammonium chloride)

IV. amphoteric surfactants including N-coco-beta-aminobutyric acid;amine oxides.

V. Solubilizers including naphtalene sulfonate; cumol sulfonate.

VI. Dispersants including phenylsulfonates; (alkyl-) naphtalenesulfonates; polycarboxylates; acrylic polymers; maleic acid/acrylic acidcoploymers; maleic acid/methyl vinyl ether copolymers; polyvinylpyrrolidone; polyvinyl pyrrolidone/polystyrene copolymers; (ethoxylated)lignin sulfonates.

It is advantageous, though not necessary, that an equilibrium of theactivities of the remaining substances in the aggregate mixture ismaintained between the first phase and the second phase. This is thecase when pure crystals of the desired substance grow and the nucleationof non-desired crystal can be inhibited completely or spontaneouslyformed nuclei of non-desired crystals are removed by filtration,ultrasound, adsorption and the like. Then the separation process of thisapplication is highly selective since only the desired substance flowscontinuously from the first phase through the second phase to the thirdphase. The undesired substances remain in the first phase since noundesired substance flows from the second to the third phase thusmaintaining an equilibrium of activities of the undesired substancesbetween the first and second phases.

The process of the present invention can, however, be practiced evenwhere there is potential for flow of one or more of the remainingsubstances to the third phase. In this event, high levels of purity ofthe desired substance can still be obtained if the flow for the desiredcomponent is significantly higher than for the undesired impurities.

Even if the obtained purity is the same or lower than in a conventional2-phase-crystallisation process, there may be still considerableeconomic interest in conducting the crystallisation as a3-phase-crystallisation process, since loss of a desired substance inmother liquid can be considerably lower than in conventional processes.

Seeding with the desired substance may take place by various methods.The seed crystals may be selected according to quantity, size, habitus,modification, molecular species (different compounds, homologues,isomers, diastereomers, enantiomers) and/or ionic compounds. The seedcrystals may also constitute mixtures of different ionic or molecularcompounds (e.g. homologues, isomers, diastereomers or enantiomers) ormay consist of crystals of different modifications, habitus, size, indifferent quantities.

During seeding, it is usually desirable to inhibit crystallisation ofnon-seeded species, which may be caused by primary or secondarynucleation.

Primary nucleation can be inhibited by a proper degree ofsupersaturation, by a proper choice and amount of surfactants andsolvents, especially solvents which serve as relatively good solventsfor the aggregate mixture in the first phase but show also—especially athigher temperature due to the higher entropy of the system—a solubilityof more than 5% in the second phase at r.t., by choice of temperatures,viscosities and agitation.

Just formed nuclei can be immediately removed e.g. by ultrasound or byremoving these tiny seeds by a filtration process or a re-homogenizationprocess with ultrasound or heat after the mother liquid has beenfiltered from the growing seeded crystals e.g. in a continuous recyclemode and/or by inhibiting secondary nucleation.

Secondary nucleation can be inhibited by proper, gentle agitation andalso by growing selectively more compact crystal forms, which do nothave a strong tendency to break into pieces, which serve as new seedcrystals for the desired components and/or offer spots and/or surfacesdue to non-homogeneous way of growth or breakage of easily breakablecrystals, where undesired crystals may start to grow.

The crystal growth rate can be optimised by the generated chemicalpotential for the crystallisation process which is dependent on thedegree of supersaturation, by the normally limited solubility of thedesired substance in the second phase, which can be controlled by aproper choice of solvents and additives, or by a proper microenvironmentadsorbed on the crystal surface, e.g. surfactants, dispersants, polymerswhich may serve as a retarding and/or selective layer or membrane.

This crystallisation process can be performed at an optimum temperaturewithin wide limits (e.g. −20° C. to +80° C.). The additives previouslymentioned may also serve as antifreeze agents.

This crystallisation process can further be optimised by a properagitation during the crystallisation (e.g. by stirring, shaking, pumpingand/or ultrasound).

After the crystallisation is complete, the precipitate can be obtainedby simple filtration and subsequent thorough washing with a solvent e.g.similar to or the same as phase 2. For example, precipitate from an o/wmicroemulsion may be washed with water, whereas precipitate from a w/omicroemulsion may be washed with oil to remove residual microemulsion,surfactant, dispersant, solvent etc. The solvent may further containadditional surfactant or dispersant to aid complete re-dispersion of thecrystalline precipitate in the washing liquid, thus making the washingprocess more efficient.

Various embodiments of the three phase system of this invention arecontemplated.

The first and second phases may comprise an “oil-in-water” (o/w) or a“water-in-oil” (w/o) dispersion. “Oil” as used herein refers to a poorlywater soluble solvent e.g. any of the poorly water-soluble solvents thathave been previously mentioned in this application. O/w and w/odispersions and methods for forming them are per se known in the art.The aggregate mixture may be conveniently combined with one or morenon-polar, amphiphilic or polar solvents such as those previouslymentioned to form a supersaturated solution of the aggregate mixture; orthe aggregate mixture may be “oil”, itself.

The surface active agent will normally be present in an amount rangingfrom 0.1 to 99% by weight preferably 3 to 33%.

Preferably the temperature of the dispersion is kept constant.Optionally the dispersion can be agitated to enhance the crystallisationprocess, or treated with gentle ultrasound to aid clean crystal growthand to destroy spontaneously formed nuclei.

A suitable means of carrying out the invention is as follows: A firstphase comprising aggregate mixture, optionally dissolved in a solvent orsolvent mixture, which is at least in part not-soluble in the secondphase is combined with a second phase and a surface active agent.Further additives may also be added where desirable, includingdispersants, antifoaming agents, solubility regulating additives,antifreeze agents and the like.

The phases are agitated to accelerate the formation of a dispersion ofmicroemulsion droplets of diameter less than 500 nm, preferably 5-200nm, of the first phase in the second phase.

After the dispersion is brought to the desired crystallisationtemperature, a suspension of one or more species of seed crystals chosenaccording to quantity, size, habitus, purity, modification, andmolecular and/or ionic composition for the crystallisation of thedesired substance of the aggregate mixture is added. The seededcomponent then crystallizes selectively within a given period of timewhile the dispersion is either left standing, or is agitated (shaken orstirred or pumped or treated moderately with ultrasound)

The separation process of the present invention may be carried out as abatch process or a continuous process. One means for carrying out theprocess continuously is illustrated with reference to FIG. 1.

The aggregate mixture is introduced as coarse solid particles (or inanother appropriate form, suitable for use in the equipment according toFIG. 1 or modifications thereof such as a coarse solid carrier coated byan aggregate liquid mixture, or as a viscous or pasty mash or a liquid)through entrance 2 of an appropriate container or column 3 batchwise orcontinuously and may be continuously transported there through. Theaggregate mixture may also be introduced as a liquid mixture or asuspension, which is pumped along e.g. a fine sieve or a porous or bydiffusion penetrable membrane, thus allowing that material is dissolvedinto the dispersion system of the 3-phase-crystallization from thissolid barrier. The microemulsion and the feed aggregate mixture in thecontainer or column 3 may be properly agitated by stirring, shaking,pumping and/or ultrasound etc. To supersaturate the microemulsion withthe desired substance or with the aggregate mixture, the microemulsionand the feed aggregate mixture in the container or column 3 may beheated e.g. at a temperature greater than in the crystalliser or may betreated with ultrasound. If the aggregate mixture is more soluble thanthe crystal of the desired compound (e.g. supercooled melt, a glassymaterial or a more soluble modification), it may be sufficient to atleast partially dissolve the aggregate mixture in the microemulsion atcrystallisation temperature to obtain a sufficient supersaturation.

Crystallisation from the microemulsion 4 is carried out in a container5, into which the third phase 6 may be introduced, e.g. in the form of aseed suspension, e.g. through an appropriate entrance 7. The dispersionin the crystalliser is kept preferably at a temperature below that inthe feed vessel 3, e.g. at 20° C. A small fraction of the microemulsionis pumped through a filter 8 in order to withhold any crystals formed inthe crystalliser, optionally through a heat exchanger 9 to increase thetemperature of the microemulsion to that of the feed vessel 3 and thenthrough the feed vessel 3 with the aggregate mixture 1 to be purified.After contact of the microemulsion with the aggregate mixture 1 over asufficient column length or a sufficient length of time, the reloadedmicroemulsion is pumped through filter 10 and optionally the heatexchanger 9 a, to adjust the temperature of the microemulsion back toits original temperature (in this example from 50° C. to 20° C.). Thedispersion in container 5 is conveniently stirred, employing aconventional stirrer 12. It may also be treated by moderate ultrasoundas means to immediately destroy nuclei formed by spontaneous nucleation.

Crystals formed may be separated by conventional means, employing e.g. acrystal separator 13 and a crystal carry out 14 (not shown) or may beclassified and separated from the dispersion by a sifter, by a cycloneor by centrifugation. The crystals may also be further separated bysieving or centrifugation into different classes of sizes. The differentsize classes may contain different crystal species (modifications,isomers, compounds) according to the specific3-phase-crystallization-process. The crystals may be washed with aliquid with a polarity e.g. similar to phase 2, where the crystals arepoorly soluble. Waste material 15 may be carried out continuously orbatchwise.

The thus described equipment for continuous supersaturation byheating/cooling may be adapted in conventional manner to an equipmentsuitable for continuous supersaturation employing ultrasound in additionto or instead of heating/cooling.

Modifications to this equipment are possible and to be considered withinthe scope of the present invention. For example, the aggregate mixture 1and the microemulsion 4 may move cocurrently, in which case the phasesshould preferably move with different velocity to allow optimum use ofthe aggregate mixture 1 and optimum supersaturation of the microemulsion4.

EXAMPLES

All compounds are used without further purification. The surfactantsRhodafac RE 610 and Soprophor FL are obtainable from Rhône-Poulenc,Surfynol 465 from Air Products, Synperonic NP 10 from ICI andNa-Laurylsulfate from Fluka. For agitation a shaking machine is used(Buhler KL Tuttlingen). Purities of the resulting crystals are measuredby using an PolarMonitor polarimeter (IBZ Hannover; ethanol as solvent;the total crystal quantity was dissolved; 1 ml cell; 20° C.)

Preparation of Example 449

45 mg of (R,R)- and (S,S)-Hydrobenzoin (HBZ; purity >97%) are dissolvedin 1 ml of a mixture of 20% v/v 2-hexanol, 12% v/v Rhodafac RE 610, 6%v/v Soprophor FL and 62% v/v water by heating to 80° C. in a 5 ml vial.After the HBZ is completely dissolved the microemulsion is cooled downto room temperature and agitated using a shaking machine (420 rpm).During two hours no spontaneous crystallisation could be observed. Themixture is then seeded with two drops of a dilute, finely groundsuspension of pure (S,S)-(−)-HBZ crystals grown under similarconditions. After 2 hours of agitation the resulting crystals arefiltered off, washed with water and dried in a gentle nitrogen stream.

The examples shown in Table A below are prepared following the procedurefor example 449, with the modifications in components and the resultsindicated.

Preparation of Example 309

35 mg of R- and S-1,1′-bi-(2-naphthol) (BNA; purity 99%) are dissolvedin 1 ml of a mixture of 9% N-methyl-pyrrolidone, 9% v/v 2-hexanol, 10%v/v Rhodafac RE 610, 5% v/v Soprophor FL and 68% v/v water by heating to50° C. in a 5 ml vial. After the BNA is completely dissolved, themicroemulsion is cooled down to r.t. and agitated with a shaking machine(350 rpm). During two hours, no spontaneous cyrstallisation can beobserved. The mixture is then seeded with two drops of a dilute, finelyground suspension of pure R(+)-BNA crystals grown under similarconditions. After two hours of shaking, the resulting crystals arefiltered off, washed with water and dried in a gentle nitrogen stream.

Yield: 5.4 mg (15.4%) colourless crystals

Purity: >90% R.

TABLE A solvent vol. HBZ amphiphilic No [ml] [mg] alcohol (vol %)solvent (vol %) surfactant 1 (vol %) 312 a 2 35 pentanol 10 Rhodafac RE610  8 312 f 2 35 pentanol 10 Rhodafac RE 610  8 312 h 2 35 pentanol 10Rhodafac RE 610  8 312 g 2 35 pentanol 10 Rhodafac RE 610  8 312 i 2 35pentanol 10 Rhodafac RE 610  8 312 j 2 35 pentanol 10 Rhodafac RE 610  8312 k 2 35 pentanol 10 Rhodafac RE 610  8 312 l 2 35 pentanol 10Rhodafac RE 610  8 312 m 2 35 pentanol 10 Rhodafac RE 610  8 312 n 2 35pentanol 10 Rhodafac RE 610  8 326 b 2 70 pentanol 20 Rhodafac RE 610 12326 c 1 35 pentanol 20 Rhodafac RE 610 12 449 b 1 40 hexanol 20 RhodafacRE 610 12 449 c 1 45 hexanol 20 Rhodafac RE 610 12 449 d 1 50 hexanol 20Rhodafac RE 610 12 478 a 1 50 hexanol 20 ethanol 5 Rhodafac RE 610 12478 c 1 50 hexanol 20 ethanol 5 Rhodafac RE 610 12 478 d 1 50 hexanol 20ethanol 5 Rhodafac RE 610 12 381 a 1 50 hexanol 20 DME 5 Rhodafac RE 61012 381 b 1 60 hexanol 20 DME 5 Rhodafac RE 610 12 381 c 1 60 hexanol 20DME 5 Rhodafac RE 610 12 381 e 1 55 hexanol 20 DME 5 Rhodafac RE 610 12381 g 1 50 hexanol 20 DME 5 Rhodafac RE 610 12 381 j 1 50 hexanol 20 DME5 Rhodafac RE 610 12 469 a 1 60 hexanol 20 DME 5 Rhodafac RE 610 16 469b 1 60 hexanol 20 DME 5 Rhodafac RE 610 16 469 c 1 60 hexanol 20 DME 5Rhodafac RE 610 16 357 a 1 40 pentanol 10 DME 5 Rhodafac RE 610 12 357 b1 50 pentanol 10 DME 5 Rhodafac RE 610 12 491 a 1 60 pentanol 20 DME 5Rhodafac RE 610 12 491 b 1 60 pentanol 20 DME 5 Rhodafac RE 610 12 492 150 hexanol 20 DME 5 Synperonic NP 10  9 494 1 50 hexanol 20 DME 5Rhodafac RE 610  9 491 1 50 hexanol 20 DME 5 Synperonic NP 10  9 493 150 hexanol 20 DME 5 Surfinol 465  9 495 1 50 hexanol 20 DME 5 SynperonicNP 10  9 no spontaneous at yield purity No surfactant 2 (vol %)crystallisation for temperature [mg] [%] [% S] comment 312 a SoprophorFL 4 >24 h  18° C. 1.6 4.6 97.4 312 f Soprophor FL 4 >3 h 18° C. 6.819.4  53.0 312 h Soprophor FL 4 >3 h 18° C. 2.6 7.4 57.0 312 g SoprophorFL 4 >3 h 18° C. 2.7 7.5 73.2 312 i Soprophor FL 4 >3 h 18° C. 2.9 8.356.5 312 j Soprophor FL 4 >1.5 h   19° C. 1.8 5.1 103.1  312 k SoprophorFL 4 >1.5 h   19° C. 1.5 4.3 89.1 312 l Soprophor FL 4 >1.5 h   19° C.1.3 3.7 70.4 312 m Soprophor FL 4 >1 h 19° C. 2.1 6.0 76.5 312 nSoprophor FL 4 >1 h 19° C. 2.4 6.9 84.6 326 b Soprophor FL 6 >1 h 18° C.1.0 1.4 92.5 326 c Soprophor FL 6 <2 h 18° C. 0.1 0.3 — spont. cryst.*449 b Soprophor FL 6 >2 h 20° C. 0.2 0.5 92.5 449 c Soprophor FL 6 >2 h20° C. 3.8 8.4 61.3 449 d Soprophor FL 6 >2 h 20° C. 3.6 7.2 92.8 478 aSoprophor FL 6 >1 h 20° C. 2.5 5.0 94.5 478 c Soprophor FL 6 >2 h 20° C.2.5 5.0 101.4  478 d Soprophor FL 6 >2 h 20° C. 4.8 9.6 61.6 381 aSoprophor FL 6 >0.5 h   17° C. 2.9 5.8 82.3 381 b Soprophor FL 6 >2 h18° C. 2.4 4.0 98.5 381 c Soprophor FL 6 >2 h 18° C. 2.5 4.2 94.4 381 eSoprophor FL 6 >2 h 20° C. 1.2 2.2 96.3 381 g Soprophor FL 6 >1 h 20° C.1.2 2.4 94.4 381 j Soprophor FL 6 >12 h  12° C. 3.3 6.6 99.4 469 aSoprophor FL 8 >2 h 20° C. 1.5 2.5 98.4 469 b Soprophor FL 8 >2 h 20° C.4.1 6.8 99.4 469 c Soprophor FL 8 >2 h 20° C. 3.7 6.2 97.5 357 aSoprophor FL 6 >1 h 18° C. 0.3  0.75 83.8 357 b Soprophor FL 6 <1 h 18°C. 5.5 11.0  — spont. cryst.* 491 a Soprophor FL 6 >2 h 20° C. 4.2 7.094.4 491 b Soprophor FL 6 <2 h 20° C. 4.5 7.5 — spont. cryst.* 492Soprophor FL 9 >1 h 20° C. 2.0 4.0 96.2 494 Aerosol OT 70 PG 9 <1 h 20°C. 1.0 2.0 — spont. cryst.* 491 Aerosol OT 70 PG 9 <1 h 20° C. 1.0 2.0 —spont. cryst.* 493 Na-Laurylsulfat 9 <1 h 20° C. 2.0 4.0 — spont.cryst.* 495 Na-Laurylsulfat 9 <1 h 20° C. 2.0 4.0 — spont. cryst.**spontaneous crystallisation, therefore no seeding

What is claimed is:
 1. A process for separating a desired substance froman aggregate mixture in which process a three phase dispersion is formedwith (i) a first phase comprising droplets containing the aggregatemixture, (ii) a second phase comprising a liquid transport phase, and(iii) a third phase comprising a surface upon which the desiredsubstance can crystallize, whereby a chemical potential exists forcrystal growth of the desired substance in the third phase therebycreating a flow of the desired substance from the first phase throughthe second phase to the third phase where the desired substancecrystallizes, wherein the Gibbs free enthalpy of formation (ΔG) of thedroplets is <0.
 2. A process according to claim 1 wherein the first andsecond phases together form a microemulsion.
 3. A process according toclaim 1 wherein the droplets have a diameter of less than 500 nm.
 4. Aprocess according to claim 1 wherein the dispersion further comprises asolvent.
 5. A process according to claim 1 wherein the dispersionfurther comprises an alcohol.
 6. A process according to claim 1 whereinthe dispersion further comprises a surface active agent.
 7. A processaccording to claim 1 wherein the third phase is formed by introducingseed crystals of the desired substance into the second phase.
 8. Aprocess according to claim 1 wherein the first and second phasescomprise an oil-in-water dispersion or a water-in-oil dispersion.
 9. Aprocess according to claim 1 carried out in batch operation.
 10. Aprocess according to claim 1 carried out in continuous operation.